The present invention relates to the production and use of a composition suitable for use in carcinoma therapy.
Although the following description refers exclusively to the Thioredoxin family of proteins, the person skilled in the art will appreciate that the present invention could also be used for other proteins and protein families that are involved in Reactive Oxygen Species (ROS) signalling pathways.
The Tumour Necrosis Factor receptor (TNFR) family, commonly known as “death receptors”, provides a popular therapeutic avenue for anti-cancer therapy. Activation by binding and/or or cross-linking of the classical death receptors, such as TNF-RI, Fas and TRAIL-R, and non-classical TNFRs, such as CD40 and Lymphotoxin-receptor (LT-R), by their cognate ligands can induce apoptosis in carcinoma cells of various tissue origins.
However, it has been found previously that recombinant soluble trimeric TNFR agonists are inefficient at killing tumour cells as they do not appear to cross-link TNFRs sufficiently to engage intracellular apoptotic signalling pathways. As such, these ligands are only cytostatic and can only be strongly pro-apoptotic in combination with pharmacological inhibitors of protein synthesis, which are highly toxic to epithelial cells. By contrast, highly cross-linked TNFR ligands, either multimeric aggregates of agonists or cell surface (membrane-presented)-delivered ligands can induce extensive killing in carcinoma cells.
However, in some cases such highly cross-linked agonists are non-specific to tumour cells and they have demonstrated severe cytotoxicity in normal cells (TNF-Related Apoptosis Inducing Ligand (TRAIL)-R agonists, for example).
One exception to this in the TNFR family members is CD40, which is uniquely tumour specific, as it has been shown to induce extensive apoptosis in malignant cells but not normal epithelial cells. However, despite this particular ability, CD40-killing requires extensive receptor cross-linking, and therefore requires cell surface-delivered ligand delivery for its activation, which due to the insolubility in aqueous systems of the surface immobilised ligand, presents a serious therapeutic obstacle.
Lin et al., 2010, Carcinogenesis, 32: 154 discloses the use of 2-tellerium-bridged beta-cyclodextrin (TeCD) compounds in combination with TRAIL ligand to kill TRAIL-resistant tumour cells by inhibition of the Trx reductase enzyme along with other enzymes (relating to the Glutathione pathway) that affect detoxifying mechanisms relating to NF-kappaB. As such this paper teaches methods to sensitize tumour cells to TRAIL by targeting (inhibiting) protective, NF-kappaB transcription factor-driven anti-apoptotic pathways. A major problem with such an approach is that targeting an enzyme poses the additional risk of tumours developing resistance to such inhibitors by mutations, as is the case with several drugs already used, such as tyrosine kinase inhibitors.